1. Field of the Invention
The present invention relates generally to cross-linking agents. More particularly, this invention relates to cross-linkers which can be used to provide high water content, optically transparent, high refractive index hydrogels which are especially useful in the fabrication of intraocular lenses. In one of its more particular aspects, this invention relates to methods for the synthesis of such cross-linkers. In another of its more particular aspects, the present invention relates to hydrogels prepared utilizing such cross-linkers.
2. Description of Related Art
Since the early 1940s, optical devices in the form of intraocular lenses have been utilized to replace the natural physiological crystalline ocular lens in humans and other mammals. Typically, the intraocular lens is implanted within the ocular environment immediately after surgically removing the natural lens which has become opaque or otherwise damaged by cataract formation or injury.
For decades the most prevalently utilized materials for forming intraocular lenses were acrylates or methacrylates and particularly polymethylmethacrylate, a rigid, glassy polymer. However, since full-size polymethylmethacrylate intraocular lenses have diameters in the range of 8-13 mm, relatively large incisions were necessary in order to remove the natural lens and insert the intraocular lens.
Recently developed surgical techniques and improved instrumentation have made it possible to remove the opaque or damaged natural lens through incision sizes as small as 2-3 mm. Because small incision surgery is much less traumatic for patients and decreases complications and healing time, this technique has become the method of choice for a large number of ophthalmic surgeons.
A number of different intraocular lens designs and materials have been developed for use in connection with small incision surgical techniques. One approach utilizes the concept of preparing lenses from elastomeric materials such as silicones and thermoplastic polymers. Prior to surgically inserting the elastomeric lens, the surgeon rolls or folds the lens so that it is reduced in size for passing into the eye through a smaller incision. Once placed within the eye, the lens unfolds or unrolls to its full size.
One problem associated with these elastomeric lenses is the possibility that permanent deformation or crease marks may occur when the lens is folded or rolled. This is especially a concern at the center of the lens optical zone where most of the rolling or folding deformation takes place.
Another approach to providing a small incision intraocular lens is suggested in U.S. Pat. No. 4,731,079. This reference discloses an intraocular lens formed of a polymer having a softening (or glass transition) temperature less than 42.degree. C. and preferably about body temperature. The lens can be heated to above its softening temperature and deformed by compression or elongation to reduce at least one dimension. Then, by cooling the lens at a temperature substantially below its softening temperature, the lens will remain in the deformed configuration until it is warmed. Ophthalmic surgeons can implant the deformed lens and once the lens warms to body temperature it returns to its original configuration. A major problem associated with these intraocular lenses is the restricted number of polymers available for preparing the lenses. Polymethylmethacrylate has a glass transition temperature of 100.degree. C. and thus cannot be used to form these lenses. Most acrylates and methacrylates have similarly high glass transition temperatures. Though formulating the lenses with plasticizers will lower the glass transition temperature, the presence of plasticizers in intraocular lenses is generally unacceptable to most surgeons because of potential leaching problems. Alternatively, water is a suitable plasticizer. However, only small amounts of water, typically less than 10%, can be utilized in the polymers to place the glass transition in the appropriate range. Thus, typical hydrogels which have much higher amounts of water are not suitable for fabricating the deformable lenses.
An additional drawback with this suggested small incision intraocular lens is the added degree of surgical complexity required to deform the lens into its small incision configuration. The lenses disclosed in U.S. Pat. No. 4,731,079 are packaged in a form that requires the implanting surgeon to warm, deform, and cool the lens immediately prior to its implantation. This procedure is considerably more involved than traditional lens implantation techniques.
Another suggested approach for small incision lens implantation involves implanting hydrogel intraocular lenses in their smaller dehydrated state. Once the implanted dehydrated lens is secured within the eye it reportedly hydrates and swells in the aqueous ocular environment. A significant problem associated with this approach is the large amount of swelling required to produce an effective lens diameter. In order to fully swell the lens from a diameter of about 3 mm to about 6 mm the lens must swell 8 times by volume. This translates to a lens which is about 85% water. For larger full sized intraocular lenses the swell volume is much higher. Since most hydrogels are structurally very weak at these high water contents, many surgeons are reluctant to implant them. Also, these high water content hydrogels have a very low refractive index, n.sub.D.sup.20, of around 1.36. In order to achieve suitable refractive powers, the hydrogel lens must therefore be thicker in the optic portion. As a result, a dehydrated hydrogel intraocular lens that will fit through a desirably small incision will not swell to a sufficiently large hydrated size to effectively function as an intraocular lens. This problem is compounded if larger, full size intraocular lenses that have optic diameters greater than 6 mm are desired. In order to produce a hydrated lens having a sufficient optic diameter the dehydrated hydrogel lens must be larger than desirable for a small incision implantation procedure. Alternatively, U.S. Pat. No. 4,919,662 suggests rolling or folding hydrogel intraocular lenses in their elastic hydrated form, and then dehydrating the lenses at lower temperatures to fix the rolled or folded lens configuration at a size suitable for small incision implantation. Once implanted, these lenses hydrate and swell to the original lens configuration. This method has the disadvantage of requiring the handling of fully hydrated lenses during the deforming process. Unfortunately, hydrated lenses have relatively weak tear strengths and handling the lenses causes frequent tearing damage.
U.S. Pat. No. 4,813,954 discloses expansile hydrogel intraocular lenses which are formed by simultaneously deforming and dehydrating hydrogel intraocular lenses prior to implanting the lenses in their dehydrated state. Lenses subjected to this treatment swell to about 180% of their reduced size. For example, lenses deformed or compressed to a diameter of 3.2 mm will swell to only about 5.8 mm. Thus, while providing some advantages over simply implanting dehydrated lenses, the method and lenses described in U.S. Pat. No. 4,813,954 do not result in full sized implanted intraocular lenses of over 8 mm.
In addition to size considerations, however, the constitution of the hydrogels must also be considered. The provision of high water content, optically transparent, high refractive index hydrogels which possess long term stability depends to a large extent upon the make-up of the hydrogel. Since most hydrogels are composed of cross-linked copolymers, the selection of appropriate comonomers is an important consideration. Moreover, whether a hydrogel will be satisfactory for a particular application also depends upon the suitability of the cross-linking agent utilized in the production of the hydrogel.
Many conventional cross-linkers are hydrophobic materials, the use of which in hydrogels reduces the water content thereof. Hydrophobic cross-linkers, in addition, may cause microphase separation in the hydrogels in which they are used, resulting in cloudy hydrogels, rather than the optically transparent hydrogels desired for many applications.
Hydrophilic cross-linkers, a number of which are commercially available, possess advantages over hydrophobic cross-linkers with respect to hydrogel water content and optical transparency. However, since known hydrophilic cross-linkers generally contain ester or amide linkages, they are subject to hydrolysis, which can adversely affect the long-term stability of the hydrogels in which they are used. Hydrolysis of the ester or amide linkages of the cross-linker promotes polymer chain scission leading to hydrogel degradation.
In general, presently available cross-linkers fall into one of two classes. They are either non-hydrolyzable, hydrophobic cross-linkers or hydrolyzable, hydrophilic cross-linkers. Since both classes of cross-linkers have disadvantages, a compromise must frequently be reached based upon the specific application for the hydrogel in which the cross-linker is used. For certain more demanding applications, however, neither class of cross-linkers is totally satisfactory, since, for optimum utilization, the cross-linker must be both non-hydrolyzable and hydrophilic.
It is therefore an object of the present invention to provide cross-linkers which are both non-hydrolyzable and hydrophilic.
Another object of this invention is to provide methods for the synthesis of such cross-linkers.
An additional object of this invention is to provide cross-linked hydrogels having the properties of high water content, high refractive index, optical transparency, and long term stability.
Other objects and advantages of the present invention will become apparent from the following disclosure and description.